tbuckley/cabot-search huggingface dataset:
P12.14.B HIGHLY INVASIVE GLIOMA CELLS MOTILITY MEASUREMENTS ON A VARIETY OF EXTRACELLULAR MATRIX PROTEINS
Authors: M Shevtsov, R Tagaeva, N Yudintceva, E Fedorov, A Kim, O Rozanov, T Garaev, K Samochernykh, D Bobkov
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma multiforme (GBM) is a heterogeneous highly invasive malignant brain tumor. The extracellular matrix (ECM) produced by tumor microenvironment plays an important role in the regulation of cell motility and invasion into surrounding healthy tissue. In this research we determined the effect of various ECM proteins on the motility of primary tumor cells. MATERIAL AND METHODS Primary tumor cells were isolated from biopsy material obtained during GBM surgical removal. Cultivation of the piece of tumor (0.5 mm3) was carried out in the form of an 3D explant model at 37°C in 5% CO2-incubator. After several months, cells migrated from the tumor spontaneously formed spheroids. To assess the rate of cell migration, spheroids were seeded on 24-well plate coated with poly-L-lysine, fibrinogen, collagen type I, and Matrigel. After 3 days, the field of view in the well (n=9) was microphotographed every 15 min for 56 hours, after which the tracks of cells outside the spheroids were manually marked (n=50) on the obtained images. The average and maximum speeds were calculated, as well as the straightness of the track (the ratio of the Euclidean distance to the track length). The Mean square displacement (MSD) was plotted against time for each protein studied in comparison with random walk simulation calculated for the equal track parameters (number of steps, mean and sd) on correspondent protein. RESULTS Live-cell imaging of the patient-derived cells revealed the heterogeneous population of actively moving cells outside the spheroids. The following results of measuring cell motility were obtained (mean ± sd): (1) Mean speed on poly-L-lysine 4.3 ± 2.5 μm/h; on fibrinogen 11.1 ± 5.7 μm/h; on collagen type I 8.8 ± 5.1 μm/h; on Matrigel 9.7 ± 3.6 μm/h. (2) Max speed on poly-L-lysine 63.8 ± 30.1 μm/h; on fibrinogen 90.0 ± 38.9 μm/h; on collagen type I 96.1 ± 42.1 μm/h; on Matrigel 84.1 ± 34.1 μm/h. (3) Straightness on poly-L-lysine 0.24 ± 0.14 μm/h; on fibrinogen 0.18 ± 0.11 μm/h; on collagen type I 0.14 ± 0.09 μm/h; on Matrigel 0.20 ± 0.12 μm/h. MSD analysis showed the greatest contribution of random walk in the motility of cells on collagen type I, the smallest - on Matrigel. CONCLUSION Proteins of ECM affect not only the speed of cell movement, but also the tortuosity of their tracks. Further studies will clarify the mechanisms of GBM invasion depending on the composition of the ECM.
P17.14.B PHASE I TRIAL OF DNX-2401 ONCOLYTIC ADENOVIRUS COMBINED WITH A SHORT COURSE OF DOSE-DENSE TEMOZOLOMIDE FOR RECURRENT GLIOBLASTOMA
Authors: J Gallego Perez-Larraya, M García-Moure, M González-Huárriz, M Zalacaín, L Marrodán, M Puigdelloses, S Labiano, D de la Nava, V Laspidea, I Ausejo, I Hervás, I Esparragosa, M Giráldez, P Domínguez, A Martínez-Simón, M Idoate, J Fueyo, C Gomez-Manzano, A Patiño, R Díez-Valle, S Tejada, M Alonso
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Oncolytic virotherapy is emerging as a novel therapeutic strategy for glioblastoma (GBM). DNX-2401, an oncolytic adenovirus with selective replication and enhanced infectivity in tumor cells, showed anti-tumor effect in a previous clinical trial for recurrent GBM. The combination of DNX-2401 and Temozolomide (TMZ) has shown a synergistic anti-glioma effect in preclinical models. MATERIAL AND METHODS We conducted a phase I open-label single-center study to investigate the safety and efficacy of this therapeutic combination in patients with first recurrence of GBM. Following tumor biopsy or resection, 3x10e10 viral particles of DNX-2401 were injected intratumorally or into the post-resection cavity, respectively. Approximately 2 weeks after DNX-2401 injection, patients were treated with up to two 28-day cycles of oral 150 mg/m2/day TMZ in a 7 days on/7 days off schedule. RESULTS Thirty-one patients (13 [42%] female, 18 [58%] male) with confirmed recurrent GBM were enrolled and treated with DNX-2401 followed by a median of 1.5 cycles of TMZ (range, 0-2). Median age was 54 years (range, 25-78) and median KPS was 70 (range 70-90). Surgery consisted of biopsy in 14, partial resection in 15 and complete resection in 2 patients. IDH1/2 mutation was confirmed in 1 patient. MGMTP was methylated in 9 and unmethylated in 21 patients (1 patient, unknown). Best response according to RANO criteria was partial response in 1 patient, stable disease in 21 subjects and progressive disease in the remainder. Median PFS was 51 days (95% CI, 43-81). Median OS was 282 days (95% CI 202-344) with 6-month and 12-month OS rates of 72.5 (95% CI 52.4-85.2) and 27.5 % (95% CI 12.4-45.0), respectively. Four patients survived more than 18 months with 2 long-term survivors exceeding 4.5 years. Treatment was generally well tolerated. The safety profile was as expected for subjects treated with TMZ alone. Except one subject who experienced grade 2 brain edema possibly related to DNX-2401, no additional toxicity was considered attributable to DNX-2401. The most frequent reported adverse events were lymphopenia (54.8%), asthenia (48.4%), constipation (41.9%), headache (29%) and pyrexia (22.6%). Ongoing correlative analyses evaluating immune response are ongoing. CONCLUSION Our data suggest that treatment with DNX-2401 followed by a short-course of dose-dense TMZ is feasible, can be safely administered with expected adverse events related to chemotherapy, and appears to render a clinical benefit in a subset of patients with recurrent GBM. Further assessment of this therapeutic approach is warranted.
P02.05.A DISSECTING THE DIFFUSE MIDLINE GLIOMA TUMOUR MICROENVIRONMENT COMMUNICATIONS USING MULTI-OMICS APPROACHES
Authors: R Collot, C Ruiz Moreno, A Wezenaar, A Zomer, H Johnson, H Stunnenberg, A Rios
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse midline glioma (DMG) represents a highly aggressive pediatric brain tumour with no chance of survival. Treatment options are urgently needed, and efforts have been put towards the development of T cell immunotherapy. However, this should consider the unique tumour microenvironment (TME) of DMG, both in terms of anatomical location and developmental stage. MATERIAL AND METHODS To gain knowledge on this unique tumour niche, we implemented an immuno-competent, syngeneic mouse model based on in-utero electroporation (IUE) of the key driver-mutations to induce tumour formation at embryonic stage. By combining snRNAseq, Spatial Transcriptomics and state-of-the-art imaging, we characterized the spatial and molecular landscape of DMG. RESULTS AND CONCLUSION We observed a high intratumoral heterogeneity with spatially restricted cell populations. Importantly, their molecular profiles correlate with patient data, illustrating the clinical relevance of the IUE model. Analysis of cell-cell communications in the TME revealed a novel signalling between DMG and immunosuppressive myeloid cells, that could impact T-cell response. Using an advanced patient-derived DMG organoid co-culture model with macrophages and engineered T-cells, we are currently investigating the role of this pathway on T-cells mediated killing of DMG organoids. Thus, this project fills a critical need to delineate and overcome the immune-suppressive environment in DMG and potentiate T cell targeting.
P06.13.B GRAPHENE NANOSHEET ENABLED REPROGRAMMING OF GLIOBLASTOMA MYELOID CELLS TO UNLOCK THE EFFICACY OF IMMUNOTHERAPY
Authors: T Kisby, M Stylianou, D Despotopoulou, H Parker, A Thawley, N Lozano, A MacDonald, K Kostarelos
Journal: Neuro-Oncology (2023)

Abstract Immunotherapy has substantiated its promise and achieved striking clinical efficacy in at least a subset of patients in several cancer types. However, in patients with glioblastoma multiforme (GBM), immunotherapies have lacked efficacy as a consequence of the highly immunosuppressive “cold” tumour microenvironment. Small, thin graphene oxide (GO) nanosheets possess notable pharmacokinetic properties in GBM including deep translocation throughout the whole tumour volume and selective internalization by tumour associated macrophages and microglia (TAMMs) following local administration. The current study aimed to investigate whether this selective nanomaterial-TAMM interaction could be exploited to reprogram the immune-microenvironment of GBM. GO nanosheets were non-covalently complexed with a TLR7/8 agonist to form a stable immunomodulatory nanosystem (imodGO) which was tested in primary macrophages in vitro, and an orthotopic syngeneic GBM model in vivo. imodGO enhanced the polarization of macrophages toward a pro-inflammatory M1-like phenotype in vitro without disrupting their phagocytic or cytokine producing capacity. A single intratumoral administration of the same nanocomplex in an intracranial GL261 model was also effective in increasing M1-like TAMMs (CD86+, MHCII+, TNFα+) while decreasing immunosuppressive M2-like TAMMs (Ym1+, Arg1+) which resulted in a wider reprogramming of the brain tumour immune-microenvironment. Repeat imodGO administration was able to significantly inhibit tumour progression highlighting the therapeutic potential of this nanomaterial enabled immunomodulatory strategy. Based on these RESULTS , imodGO has emerged as a novel strategy to ameliorate the immunosuppressive character of GBM. Further work is warranted to assess whether imodGO could enhance the efficacy of systemic immunotherapies used in combination.
P10.36.B ROLE OF AMPK IN GLIOBLASTOMA BIOENERGETICS
Authors: S Caamaño-Teixeira, C Iglesias, V Gonzalez-Alvarez, V Arce, J Costoya, R Señaris
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most prevalent and aggressive primary brain tumor. AMP-activated kinase (AMPK), the main energy sensor of the cell, has been previously described by our group as a key factor in glioblastoma oncogenesis and proliferation and is known for taking part in tumoral metabolic transformation. Our group has also formerly reported how AMPK regulates the expression of lipoprotein receptors and alters lipid reliance of glioblastoma cells, suggesting AMPK orchestrates nutrient dependency and flexibility on glioblastoma. Overall, this evidence positions AMPK inhibition as a promising antitumoral therapy for glioblastoma. MATERIAL AND METHODS To further study the role of AMPK in glioblastoma bioenergetics, we used the human glioblastoma cell lines U87 and U373 and silenced AMPK by transfecting the cells with a siRNA for AMPKα1/2. To assess mitochondrial function (OCR), fuel oxidation, and glycolytic parameters (ECAR), we carried out Seahorse metabolic analyses. This technology provides non-invasive and real-time monitoring of glycolytic and mitochondrial metabolic profiles. The expression of genes related to mitochondrial energetics (CPT1C, PPARGC1A, and PPARA) in these cells was studied using RT-qPCR. We are also currently studying lactate dehydrogenase (LDH) function and expression, as well as glutamine metabolism. RESULTS Our data show that silencing of AMPKα1/2 reduces basal and maximum mitochondrial respiration, as well as decreases the expression of CPT1C, PPARGC1A, and PPARA. Altogether, these results suggest alterations in mitochondrial energetic pathways. Our results do not reveal a significant effect of AMPK on the glycolytic activity of these glioblastoma cell lines. Finally, we found a great capacity of these cells to use glucose, but also fatty acids and glutamine as energy substrates, although with a very high dependency on glucose. CONCLUSION Even though in glioblastoma cells there is an increment in aerobic glycolysis (Warburg effect), these tumoral cells still maintain an elevated mitochondrial activity and a great capacity to use lipids as a fuel. AMPK plays an important role in regulating glioblastoma mitochondrial activity and bioenergetics. The authors would like to acknowledge the Funding for the Consolidation of Competitive Groups of Research (ED431B 2020/26, Xunta de Galicia, 2020-2022).
P11.20.B ASSOCIATION OF HAND-FOOT SKIN REACTIONS WITH SURVIVAL IN RECURRENT GLIOBLASTOMA PATIENTS TREATED WITH REGORAFENIB
Authors: J Werner, P Hau, T Kowalski, H Treiber, P Roth, M M Wollring, I Stetter, C Tscherpel, E K Rosen, G S Ceccon, C I Chapuy, U Schlegel, M Weller, G R Fink, N Galldiks
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The phase 2 REGOMA trial suggested a survival benefit of the multikinase inhibitor regorafenib for the treatment of patients with glioblastoma at first recurrence. Hand-foot skin reactions (HFSR) following multikinase inhibitor therapy have been reported as a predictor for prolonged survival in patients with solid tumors. Data on the predictive value of HFSR in patients with recurrent glioblastoma undergoing regorafenib therapy remain scarce. MATERIAL AND METHODS Fifty-seven patients (age range, 35-77 years) with recurrent IDH-wildtype glioblastomas were retrospectively identified from five centers in Germany and Switzerland. Regorafenib was administered at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustments according to toxicity. Patients were stratified into two groups based on the occurrence of HFSR following regorafenib. Group differences were investigated using the Mann-Whitney rank-sum test and Fisher's exact test. Kaplan-Meier analysis was used for univariate analyses, and the Cox proportional hazards regression model for multivariate analyses. RESULTS Patients received a median of two regorafenib cycles (range, 1-14 cycles). Median follow-up after recurrence was 7.0 months (range, 0.6-35.9 months). The median number of previous treatment lines was 2 (range, 1-6 lines). At the time of data analysis, 47 patients (82%) had died. HFSR were observed in 14 of 57 patients (25%) and was associated with a significantly longer OS (10.6 vs. 6.0 months; P=0.040). No significant group differences (HFSR compared to no HFSR) were observed regarding age, the extent of resection, MGMT promoter methylation, Karnofsky performance status, or number of completed regorafenib cycles (all P&amp;gt;0.05). Cox proportional hazards regression analysis confirmed that HFSR were associated with longer OS (P=0.039; HR, 0.438), independent of age, Karnofsky performance status, and the number of previous treatment lines (all P&amp;gt;0.05). CONCLUSION Our results suggest that the occurrence of HFSR following regorafenib is associated with longer OS in recurrent glioblastoma patients.
P21.06.A TIME IN ONCOLOGY. GLIOBLASTOMA REAL-WORLD DATA
Authors: M Macià i Garau, A Lucas Calduch, N García Expósito
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Time is a crucial component in all diagnostic and therapeutic processes of cancer. Retard in the treatment can have adverse consequences on outcomes. Total treatment delays could be due to patient interval (from the first perceived symptom to the first medical consultation) and system interval (from the first medical consultation to end of treatment). To minimize delays, it is essential to know the time intervals elapsed between each of the steps in the diagnostic and the treatment phase.The purpose of this pilot study is to holistically analyze the total treatment interval of cancer patients as a part of process-oriented total quality management with the ultimate intention of having more useful information for benchmarking and making decisions to improve time in oncology. MATERIAL AND METHODS During 2019 in a context of public health-care system all relevant clinical pathway time data from the patient’s perceived first symptom until the end of oncological treatment were collected in a prospective cohort of newly diagnosed glioblastoma patients. Clinical pathway is defined as a description of the current practice in an homogeneous patient group treated by a multidisciplinary team and an inventory of actions defining a diagnostic and therapeutic sequence. This cohort was compared with a serie of glioblastoma patients treated in 2020 (COVID-19-year). We analyzed the mean, median and quartile data of 16-time intervals represented on a time scale RESULTS From January 1 to December 31, 2019, we collected data from 59 patients diagnosed and treated for a glioblastoma. There were 24 women and 35 men with a mean age of 60,9 years. We collected 1062 time-points. This group was compared with a COVID-19-year cohort of 49 patients (14 women and 35 men with a mean age of 61,7 years and 630 time-points). The median patient interval time and the system interval time were 6 days (0-210) vs 5 (0-150) and 240 days (81-363) vs 255 (120-482) respectively. Median time from surgery to the start of adjuvancy was 34 days (19-56) vs 34 (17-108). No differences were found in any of the intervals analyzed, in the overall treatment time of radiotherapy or in the dose intensity of chemotherapy. CONCLUSION The routine measurement of the intervals between the different diagnostic and therapeutic actions is essential to monitor the time of clinical processes in terms of quality and benchmarking. It is also essential to standardize in a holistic way the distressing temporality in oncology.
PL02.3.A NRG ONCOLOGY STUDY BN007: RANDOMIZED PHASE II/III TRIAL OF IPILIMIUMAB (IPI) PLUS NIVOLUMAB (NIVO) VS. TEMOZOLOMIDE (TMZ) IN MGMT-UNMETHYLATED (UMGMT) NEWLY DIAGNOSED GLIOBLASTOMA (NGBM)
Authors: A B Lassman, M C Polley, F M Iwamoto, A E Sloan, T J C Wang, K D Aldape, J S Wefel, V Gondi, A N Gutierrez, M Manasawala, M R Gilbert, E P Sulman, J D Wolchok, R M Greene, E C Neil, R V Lukas, S A Goldlust, M Snuderl, J J Dignam, M Won, B Movsas, M P Mehta
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND New therapies are especially needed for uMGMT nGBM. NRG Oncology BN002 (phase I) demonstrated safety and preliminary efficacy of Ipi+Nivo for nGBM, leading to BN007 as phase II/III. METHODS Adults with uMGMT nGBM (WHO 2016) and KPS ≥ 70 were randomized to RT and concurrent and adjuvant Ipi+Nivo or TMZ, stratified by glioma-recursive partitioning analysis class (RPA), intent to use tumor-treating fields (NCT04396860). Phase II primary endpoint was progression-free survival (PFS), powered 95% to detect a hazard ratio (HR) ≤0.58 with 1-sided 0.15 significance after 100 events. If p&amp;lt;0.15, then phase III would accrue with overall survival (OS) as primary endpoint. Corticosteroids were disallowed at Ipi+Nivo start. Histology, biomarkers, and PFS were assessed centrally. RESULTS Among 374 patients screened, 159 were randomized in phase II (79 Ipi+Nivo, 80 TMZ). Demographics (age median 60 years, range 28-79; male 66%, white 88%, not Hispanic/Latino 89%), KPS (90-100 61%), extent of resection (gross total 65% per local PI), and RPA (III 10%, IV 73%, V 17%) were well-balanced between arms. After 100 PFS events, the pre-planned phase II analysis demonstrated no improvement for Ipi+Nivo vs. TMZ [median 7.7 (95% CI: 6.5, 8.5) vs. 8.5 (95% CI: 7.1, 10.4) months; HR 1.47 (95% CI: 0.98-2.2); 1-sided p=0.96]. OS is immature (&amp;gt;50% alive, 13.7 months median follow-up) but without observed difference between arms [median ~13 months each; HR 0.95 (95% CI: 0.61-1.49); 1-sided p=0.36]. On the Ipi+Nivo arm, treatment-related grade 3, 4, and 5 events were reported in 26 (33.3%), 4 (5.1%), and 2 (2.6%; colitis and autoimmune disorder, n=1 each) patients. CONCLUSION Ipi+Nivo did not improve PFS for uMGMT nGBM. Accrual permanently closed after phase II. No new safety signals were identified. Molecular analyses and survival follow-up are ongoing. Funded by NCI Grants U10CA180868, U10CA180822, U24CA196067 (NRG Oncology Operations, SDMC, Specimen Bank).
P08.10.B COIMBRA: THE IMPACT OF RADIOTHERAPY ON QUALITY OF LIFE AND DISEASE PROGRESSION IN PATIENTS WITH BRAIN METASTASES AND THEIR CAREGIVERS
Authors: F Cialdella, E E van Grinsven, A T J van der Boog, S H J Nagtegaal, E J Smid, A Claes, C E Kleynen, E Seravalli, M E P Philippens, M J E van Zandvoort, J J C Verhoeff
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and this incidence is expected to rise due to advancements in primary tumor management. Besides improving survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. DESIGN/ METHODS The prospective COIMBRA study is designed to monitor a cohort of patients with BMs and their caregivers who are referred to a tertiary academic radiation oncology department (ClinicalTrials.gov Identifier: NCT05267158). The study is designed according to the Trials within Cohorts (TwiCs) framework, an adaptive design that allows for the evaluation of multiple interventions over time. Patients receive state of the art treatment, which includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Clinical data, QoL and cognitive functioning are collected at baseline and at regular intervals post-treatment. Additionally, new MRI techniques can be evaluated for their feasibility and performance in patients with BMs. PRELIMINARY RESULTS Since April 2019, 419 patients have been included of whom 51.2% were men and the majority of the patients had lung cancer (53.6%). SRS was administered in 92.4% and 68.1% received systemic therapy. Median overall survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before treatment (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patients’ diagnosis. CONCLUSION Our study successfully collected in-depth clinical and QoL data from patients with BMs and their caregivers. The results suggest a modest improvement in anxiety and QoL after SRS. These findings highlight the need for ongoing evaluation of interventions in this patient population in order to ultimately guide personalized treatment strategies.